Palmitoylacyltransferase Zdhhc9 inactivation mitigates leukemogenic potential of oncogenic Nras

Liu, P; Jiao, Bo; Zhang, R; Zhao, Hongchao; Zhang, C; Wu, Min; Li, D; Zhao, Xuemei; Qiu, Qingsong; Li, J.; Ren, Ruibao

doi:10.1038/leu.2015.293

Cited by 54 publications

(54 citation statements)

References 15 publications

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“…Indeed, GOLGA7 has been identified as a selective dependency in NRAS‐mutant human AML cell lines, highlighting the importance of accessory subunits in ZDHHC function . In mice lacking Zdhhc9 , Nras G12D ‐driven T‐cell acute lymphocytic leukemia and chronic myelomonocytic leukemia are both significantly attenuated but not completely prevented . The incomplete phenotypic suppression implies that additional PATs likely palmitoylate Nras in vivo .…”

Section: Protein Palmitoylation and Cancer: Connecting The Dotsmentioning

confidence: 99%

“…In mice lacking Zdhhc9 , Nras G12D ‐driven T‐cell acute lymphocytic leukemia and chronic myelomonocytic leukemia are both significantly attenuated but not completely prevented . The incomplete phenotypic suppression implies that additional PATs likely palmitoylate Nras in vivo .…”

Section: Protein Palmitoylation and Cancer: Connecting The Dotsmentioning

confidence: 99%

“…Cancer links is defined broadly as any literature link between a ZDHHC‐family member and a particular cancer, including large‐scale and small‐scale experimental studies, animal and cell culture studies, and clinical studies, whether functional or correlative. References: ZDHHC2 , ZDHHC3 , ZDHHC5 , ZDHHC7 , ZDHHC9 , ZDHHC11 , ZDHHC13 , ZDHHC14 , ZDHHC20 , ZDHHC23 .…”

Section: Introductionmentioning

confidence: 99%

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Protein palmitoylation and cancer

2018

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Protein S-palmitoylation is a reversible post-translational modification that alters the localization, stability, and function of hundreds of proteins in the cell. S-palmitoylation is essential for the function of both oncogenes (e.g., NRAS and EGFR) and tumor suppressors (e.g., SCRIB, melanocortin 1 receptor). In mammalian cells, the thioesterification of palmitate to internal cysteine residues is catalyzed by 23 Asp-His-His-Cys (DHHC)-family palmitoyl S-acyltransferases while the removal of palmitate is catalyzed by serine hydrolases, including acyl-protein thioesterases (APTs). These enzymes modulate the function of important oncogenes and tumor suppressors and often display altered expression patterns in cancer. Targeting S-palmitoylation or the enzymes responsible for palmitoylation dynamics may therefore represent a candidate therapeutic strategy for certain cancers.

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Section: Protein Palmitoylation and Cancer: Connecting The Dotsmentioning

confidence: 99%

Section: Protein Palmitoylation and Cancer: Connecting The Dotsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein palmitoylation and cancer

2018

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“…The requirement for palmitoylation in Ras-driven tumors has been tested in models of NRAS-driven leukemia, where palmitoylation of NRAS G12D was necessary for leukemogenesis (80, 81). A similar approach to investigate palmitoylation of KRAS4A G12D in leukemogenesis revealed that even in the absence of palmitoylation, the polybasic region cooperates sufficiently with prenylation to promote disease, albeit with a notable delay in disease onset (82).…”

Section: Constitutive C-terminal Modifications: Membrane Association mentioning

confidence: 99%

Posttranslational Modifications of RAS Proteins

Ahearn

Zhou

Philips

2018

Cold Spring Harb Perspect Med

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The three human RAS genes encode four proteins that play central roles in oncogenesis by acting as binary molecular switches that regulate signaling pathways for growth and differentiation. Each is subject to a set of post-translational modifications (PTMs) that modify their activity or are required for membrane targeting. The enzymes that catalyze the various PTMs are potential targets for anti-RAS drug discovery. The PTMs of RAS proteins are the focus of this review.

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“…NRAS, HRAS, and KRAS4A are further palmitoylated on the Golgi, increasing their affinity to bind the plasma membrane (16,17). We have shown previously that interrupting the plasma membrane localization of NRAS and KRAS4A could significantly abrogate their leukemogenic potential (18)(19)(20). However, the exact mechanism of RAS proteins translocating from endomembranes to the plasma membrane is still elusive (17).…”

Section: Introductionmentioning

confidence: 99%

N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation

Huang

Zhang

et al. 2017

Molecular Cancer Therapeutics

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RAS oncogenic mutations are common in human cancers, but RAS proteins have been difficult to target. We sought to identify pharmacological agents to block RAS oncogenic signaling by a distinct mechanism. Because the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we screened a bioactive lipid library using a RAS-specific cell viability assay. We report the discovery of a new class of inhibitors for RAS transformation. Compounds in the class represented by endocannabinoid N-arachidonoyl dopamine (NADA) can induce cell oncosis, independent of its ability to engage cannabinoid receptors. Further analyses show that NADA is more active in inhibiting the NRAS transformation and signaling than that of KRAS4B. Mechanistically, NADA blocks the plasma membrane translocation of NRAS, but not that of KRAS4B. In addition, NADA inhibits plasma membrane translocation and neoplastic transformation of oncogenic KRAS4A. Interestingly, NADA also redistributes the cytoplasmic NRAS to the Golgi apparatus in a palmitoylation-dependent manner. The results indicate that NADA inhibits NRAS and KRAS4A plasma membrane translocation by targeting a novel molecular process. The new findings would help to develop novel targeted therapies for a broad range of human cancers.

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Palmitoylacyltransferase Zdhhc9 inactivation mitigates leukemogenic potential of oncogenic Nras

Cited by 54 publications

References 15 publications

Protein palmitoylation and cancer

Protein palmitoylation and cancer

Posttranslational Modifications of RAS Proteins

N-Arachidonoyl Dopamine Inhibits NRAS Neoplastic Transformation by Suppressing Its Plasma Membrane Translocation

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